LSI builds structural biology dream team

ANN ARBOR, Mich.—Form is said to follow function in
architectural design, but in nature, the form and the function are often the
same thing. Individual
molecules in the tiny, complex world of the living cell interact and fit together
very specifically, based on their three-dimensional shapes.

The science of figuring out what those shapes are and how they fit together
is known as structural biology, and it holds great promise for unraveling a
host of human diseases. Misshapen proteins are known to be a factor in Alzheimer’s
and Parkinson’s, diabetes, high cholesterol, mad cow disease, bacterial
infections and are probably involved in countless other conditions as well.

The Life Sciences Institute at the University of Michigan is building one
of the nation’s foremost teams of structural biology researchers and
starting a Center for Structural Biology.

With the hiring of Janet L. Smith from Purdue University and Gabrielle Rudenko
from the University of Texas Southwest Medical Center, the LSI now has a core
of five leading structural biologists clustered around state-of-the-art facilities
on the third and fourth floors of the new LSI building.

“I love to think about biology in terms of structure,” said Smith,
who recently participated in a team effort to figure out how bacteria convert
sunlight into energy. Her current structural work focuses on an enzyme that
catalyzes chemical reactions, and on the structures used by RNA-based viruses
including West Nile, yellow fever and dengue.

The mainstay technology used by Smith and other structural biologists is x-ray
crystallography. Though today’s equipment is much better, this is essentially
the same method used by Rosalind Franklin to take the fuzzy pictures of DNA
from which James Watson and Francis Crick deduced the molecule’s elegant
double-helix shape more than 50 years ago.

A focused beam of x-ray light is shot at a crystal of pure protein. Sensitive
detectors then capture the scatter pattern that reflects off the individual
atoms in that crystal. LSI structural biologist Jeanne Stuckey likens it to
shining a light on a disco ball. With some complex math called “fast
Fourier transforms,” crystallographers are able to infer the relationships
between atoms in the crystal by the way the scattered light came off it, and
then go on to infer from that the shape of the protein.

Stuckey’s lab on the third floor of LSI has an x-ray crystallography
beam that is about 10 feet long. But at the Argonne National Laboratory’s
particle accelerator southwest of Chicago, Michigan researchers are about to
begin making images with a new x-ray beam line that will be a billion times
brighter than the tabletop version at the LSI. This will allow them to capture
finer resolution of images, and robotic sample handing machines will enable
much higher throughput of crystals.

The heavy math is only half the battle. Before they can take the picture,
researchers need to grow a nice crystal of 100 million proteins “aligned
in a beautiful, symmetrical form,” Stuckey said. In theory, at least,
any protein can be crystallized, but purifying the protein and then finding
the right conditions to grow a high quality crystal can be arduous. “It
takes a lot of patience,” Stuckey said.

Janet Smith will lead a new Protein Production Facility on LSI’s third
floor that should streamline and speed up the process by using a lot of automation.
The protein production facility will serve both the Center for Structural Biology
and researchers in the newly established Center for Chemical Genomics.

“We use automation to try many things at once for finding ideal crystal-growing
conditions,” Smith said. “That way, we don’t burn up all
our student and post-doc time just growing crystals.”

The Life Sciences Institute’s structural biologists are:

Rowena Matthews -- In work ranging from organic chemistry
to genetics, Matthews investigates the role vitamins play in the chemical reactions
in the body. Her understanding of folic acid’s biochemical role in heart
disease led to a federal policy requiring U.S. grain products to include folic
acid supplements. Since the adoption of the policy, the Centers for Disease
Control estimates the folic acid supplements are preventing nearly 50,000 deaths
annually from stroke and heart attack. She is a research professor in LSI and
biophysics and a Distinguished University Professor in Biological Chemistry.

Gabrielle Rudenko – A structural examination of protein
molecules is helping Rudenko to understand the brain. Her latest work is focused
on a class of proteins that help the brain recover from physical and chemical
insults. Rudenko, who moved into her LSI lab in April, d also has plans to
study macromolecules that are crucial to the brain, and influence how we function
and feel. She is an assistant research scientist in LSI and an assistant professor
in pharmacology.

Janet Smith – Smith has worked on difficult puzzles
of the three-dimensional shapes of biomolecules across a wide range of biology.
Her current work focuses on some very dynamic enzyme systems where a single
molecule may be involved in several different chemical reactions. She is also
working on the structures within RNA viruses that enable them to evade immune
systems and steal resources from healthy cells. She is a research professor
and leader of the protein production facility in the LSI, professor in the
Department of Biological Chemistry.

Jeanne Stuckey – In addition to supervising the x-ray
crystallography lab that assists researchers all over the U-M campus with their
structural biology questions, Stuckey is working on the structure of proteins
involved with programmed cell death. She has contributed ?structures to our
understanding of arthritis and diabetes, and the molecular tool kit of Yersina
pestis, the virulent bacterium that caused the Black Plague. Stuckey is
an assistant research scientist in LSI, biophysics, and biological chemistry.

Zhaohui Xu – Calling on tools from biology, chemistry
and physics, Xu works to understand how proteins become folded into their proper
shapes and are delivered to the right place in the cell. His lab has found
that molecular “chaperones” assist folding and transportation at
almost every step. Xu is also turning his attention to naturally occurring
enzymes and the possibility of slightly changing their folding to alter their
properties. Xu is an assistant research scientist in LSI and an assistant professor
inbiological chemistry.